Breast Cancer(s) Heterogeneity and Personalized Treatments

Image used with permission of Dr. Hongdi Liu.
Image used with permission of Dr. Hongdi Liu.
Recently Promega hosted a special guest from Duke University—Dr. Neil. L. Spector, one of leading scientists in the field of breast cancer research. In a simple way  Dr. Spector presented advances in this field of cancer research and informed us of new treatments that have the potential to improve patient lives.

For long time chemotherapy was used in high dosses that were extremely destructive for healthy parts of the body. The Maximum Tolerated Dose (MTD) was the basis of selecting the dose to be used on patient with hope that cancer cells will be killed as well. This was called “no pain – no gain” therapy. Unfortunately, this therapy was far from being very efficient. Patients who had to go through the pain of this therapy without curing the disease were harmed – not helped. In his presentation, Dr. Spector emotionally explained the responsibility of a doctor who should not harm patient more than necessary.

Initial results of drugs used in chemotherapy were promising but soon some cancers developed multi drug resistance (MDR).The reason why chemotherapy was not always efficient is the complexity and heterogeneity of cancer. One drug kills certain cancer cells in isolation (culture), but tumors, especially solid ones, are composed of different cells with various mutations, and they frequently develop resistance to drugs. This is cancer’s survival mechanism. Enormous effort of a wide research community provided comprehensive molecular portraits of human breast tumours that clarified subtypes of the diseases. These portraits give us much better understanding of regulatory pathways in cancers and enable doctors to apply personalized therapy to the treatment of cancer.

Image used with permission of Dr. Hongdi Liu.
Image used with permission of Dr. Hongdi Liu.
Dr. Spector presented the development of therapies targeting Human Epidermal Growth Factor Receptor (HER) tyrosine kinases as an example. The HER family members (HER1 or EGFR; HER2; HER3) are switches that exist on the surface of a cell.  Their deregulation results in the development and maintenance of many common solid tumors (e.g., breast cancer, non-small cell lung cancer). The research performed in these receptors and the pathways that they regulate has prompted the development of HER targeted therapies—biologics and small molecule kinase inhibitors—some of which are currently used in the clinic (e.g., trastuzumab, lapatinib, erlotinib). However, the existence of drug alone is not sufficient, and Dr. Spector spoke of the opportunities and challenges associated with the development of companion diagnostics and biomarkers to guide the clinical use of targeted therapies.

The very first step in curing any disease is to collect all possible information and establish the correct diagnosis.  Conventional diagnostics for breast cancer are based on the biopsy of solid tumor and the analysis of few receptors that regulate tumor pathways. Diagnostics based only on the expression of three biomarkers: estrogen receptors (ERs), progesterone receptors (PRs) and human epidermal growth factor receptor 2 (HER2) may soon give way to diagnoses that describe breast cancer subtypes. Thus, when speaking of triple negative breast cancer subtypes that go beyond these three standard markers will influence treatment choices.

Dr. Spector stresses the importance of an old-new marker HRG2 (heregulin2) – a polypetide ligand that regulates HER2 and HER3. HRG2 is important because, when accompanied with other markers, it predicts the severity of disease. Increase of this marker in combination with others indicates resistance of the particular cancer to certain drugs. Dr. Spector urges for the introduction of this biomarker into clinics.

Another important aspect of modern diagnostics is to detect micro metastatic disease. This can be diagnosed by detecting circulating tumor cells from blood that is further subjected to sequence profiling. There are a few methods commercially currently available that can detect 1 tumor cell in a million or in 10 million blood cells, but even greater sensitivity of detection is desired. A method that would detect one tumor in 100 million cells is still in clinical development.

Finally, molecular profiling of all tumor sites can allow a personalized treatment. This can be achieved by noninvasive imaging in real time and molecular profiling of each cancer. There are numerous tools used for diagnostics. Biomarker gene sets are used together with new methods that compute metasignatures for transcription factors and histone modifications that upregulate genes in cell lines or tumors. There are new drugs for breast cancer subtypes targeting driver pathways to overcome resistance.

All of these advances in scientific understanding, therapeutics and diagnostics work together to improve breast cancer treatment and outcomes.

Literature Cited

Stagg, J. and Allard, B. (2013) Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects  Ther Adv Med Oncol. 5, 169–181.

Duan, Q. et al. (2013) Metasignatures identify two major subtypes of breast cancer. CPT Pharmacometrics Syst Pharmacol  2, e35.

Curigliano, G. (2012)  New drugs for breast cancer subtypes: targeting driver pathways to overcome resistance.  Cancer Treat Rev. 38,303–10.

Le, X.F., Varela, C.R. and Bast, R.C. (2002) Heregulin-induced apoptosis 7, 483–491.

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Nives Kovacevic

Nives is a Promega Technical Service Scientist. She was born and educated in Knin, Croatia, where she developed her love of science and music. After completing her Agronomy studies at University of Belgrade, Serbia, Nives was a high school teacher in her home town. After her teaching experience, she continued her graduate studies at Aristotle University of Thessaloniki, Greece. She then continued with post doctoral training at UW-Madison in maize epigenetics. Today Nives lives in Middleton, Wisconsin, with her husband and enjoys hiking, swimming and skiing in the nearby bluffs, lakes and hills. The warm society and rich cultural life of Madison is a perfect environment for them.

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